Metal Ion Homeostasis

Transition metal ions are essential cofactors for proteins with diverse functions, including electron transfer, dioxygen binding and activation, nitrogen fixation, and antioxidant defense.¹ However, metal ions can also be deleterious. The dual nature of metal ions derives from two properties. First, redox active metal ions such as copper and iron can generate highly reactive hydroxyl radicals and cause oxidative damage to proteins, nucleic acids, and lipids. Second, metal ions can bind nonspecifically to amino acid residues, replacing existing metal ions in enzyme active sites or key structural sites, leading to aberrant activity or protein misfolding. Therefore, intracellular transition metal ion concentrations must be controlled carefully to ensure that metal ions are provided to essential metalloproteins and metalloenzymes, but do not accumulate to toxic levels. Since the early 1980s, a number of metal homeostatic systems in both eukaryotes and prokaryotes have been discovered by genetic techniques. Understanding these systems on the molecular level is a fundamental problem in biological coordination chemistry. Moreover, an increasing number of human diseases are linked to deficiencies in metal handling.² Proteins involved in metal ion homeostasis can be divided into two broad families, metal trafficking proteins and metalloregulatory proteins. The metal trafficking proteins include membrane transporters that translocate metal ions across cell membranes² and soluble metallochaperone proteins that deliver metal ions to specific target proteins.³ The metalloregulatory proteins utilize metal ions to regulate gene expression.^4,5 Proteins in both families maintain concentrations of both essential and nonessential metal ions. The coordination chemistry of metal homeostatic proteins is....